PerspectiveCANCER

How to lose tumor suppression

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Science  09 Aug 2019:
Vol. 365, Issue 6453, pp. 539-540
DOI: 10.1126/science.aay4319

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Summary

The tumor suppressor gene, TP53, is the most commonly mutated gene in human cancer. The resulting loss of activity of the encoded protein, p53, causes genetic instability and resistance to chemotherapy. TP53 mutations are mostly single-nucleotide point mutations that alter one amino acid, rather than deletions. These missense mutations can cause loss of function (LOF) but do they also exert dominant-negative effects (DNEs) and confer additional neomorphic gain of function (GOF) to p53? On page 599 of this issue, Boettcher et al. (1) present a comprehensive analysis of the effects of 7860 p53 point mutations in myeloid malignancies. They find clear evidence for LOF and DNEs but no evidence for GOF because the DNEs select for the spectrum of mutations found in human myeloid malignancies. Therefore, p53 GOF does not explain the mutational spectrum of TP53 despite strong evidence for their importance in mice (2)

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